Hypoxia-inducible Factor 1 as one of the “Signaling Drivers” of Toll-like Receptor-Dependent and Allergic Inflammation

  • Vadim V. Sumbayev
  • Sally A. Nicholas


Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription complex which plays a crucial role in cellular adaptation to low oxygen availability. In the last years there has been increasing evidence about the role of this factor in inflammatory/innate immune reactions. It has also been found to contribute to different types of allergic inflammation. In this review the current knowledge about the accumulation and role of HIF-1 in Toll-like receptor-mediated and allergic inflammation is summarized. Differential biochemical mechanisms employed to stabilize the protein in different cases are discussed.


Inflammation Allergy Toll-like receptors Hypoxia HIF-1 



We apologize to those researchers whose primary studies that form the basis of our current knowledge in the discussed field could not be cited due to space limitations or were indirectly acknowledged by quoting current reviews. This work was supported by the Royal Society (grant number RG080474 to Dr. V. Sumbayev) and by the start-up grant provided to Dr. Sumbayev by the Medway School of Pharmacy, University of Kent.


  1. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511CrossRefPubMedGoogle Scholar
  2. Beutler B (2004) Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430:257–263CrossRefPubMedGoogle Scholar
  3. Blouin CC, Page EL, Soucy GM et al (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha. Blood 103:1124–1130CrossRefPubMedGoogle Scholar
  4. Cramer T, Yamanishi Y, Clausen BE et al (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657CrossRefPubMedGoogle Scholar
  5. Crivellato E, Travan L, Ribatti D (2009) Mast cells and basophils: a potential link in promoting angiogenesis during allergic inflammation. Int Arch Allergy Immunol 151:89–97CrossRefPubMedGoogle Scholar
  6. Dehne N, Brune B (2009) HIF-1 in the inflammatory microenvironment. Exp Cell Res 315:1791–1797CrossRefPubMedGoogle Scholar
  7. Djafarzadeh S, Spirig R, Regueira T et al (2008) Induction of hypoxia inducible factor 1α by Toll-like receptors in human dendritic cells. Crit Care 12:S1–S151CrossRefGoogle Scholar
  8. Epstein AC, Gleadle JM, McNeill LA et al (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54CrossRefPubMedGoogle Scholar
  9. Falcone FH, Haas H, Gibbs BF (2000) The human basophil: a new appreciation of its role in immune responses. Blood 96:4028–4038PubMedGoogle Scholar
  10. Frede S, Stockmann C, Freitag P et al (2006) Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB. Biochem J 396:517–527CrossRefPubMedGoogle Scholar
  11. Galli SJ, Grimbaldeston M, Tsai M (2008) Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 8:478–486CrossRefPubMedGoogle Scholar
  12. Garlanda C, Anders HJ, Mantovani A (2009) TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization. Trends Immunol 30:439–446CrossRefPubMedGoogle Scholar
  13. Gay NJ, Gangloff M (2007) Structure and function of Toll receptors and their ligands. Annu Rev Biochem 76:141–165CrossRefPubMedGoogle Scholar
  14. Gould HJ, Sutton BJ, Beavil AJ et al (2003) The biology of IGE and the basis of allergic disease. Annu Rev Immunol 21:579–628CrossRefPubMedGoogle Scholar
  15. Gray P, Dunne A, Brikos C et al (2006) MyD88 adapter-like (Mal) is phosphorylated by Bruton’s tyrosine kinase during TLR2 and TLR4 signal transduction. J Biol Chem 281:10489–10495CrossRefPubMedGoogle Scholar
  16. Grimbaldeston MA, Metz M, Yu M et al (2006) Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses. Curr Opin Immunol 18:751–760CrossRefPubMedGoogle Scholar
  17. Hayakawa T, Matsuzawa A, Noguchi T et al (2006) The ASK1-MAP kinase pathways in immune and stress responses. Microbes Infect 8:1098–1107CrossRefPubMedGoogle Scholar
  18. He H, Genovese KJ, Nisbet DJ et al (2006) Involvement of phosphatidylinositol-phospholipase C in immune response to Salmonella lipopolysacharide in chicken macrophage cells (HD11). Int Immunopharmacol 6:1780–1787CrossRefPubMedGoogle Scholar
  19. Huang LE, Gu J, Schau M et al (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95:7987–7992CrossRefPubMedGoogle Scholar
  20. Ivan M, Kondo K, Yang H et al (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468CrossRefPubMedGoogle Scholar
  21. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995CrossRefPubMedGoogle Scholar
  22. Jaakkola P, Mole DR, Tian YM et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472CrossRefPubMedGoogle Scholar
  23. Jantsch J, Chakravortty D, Turza N et al (2008) Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol 180:4697–4705PubMedGoogle Scholar
  24. Jelkmann Y (2004) Molecular biology of erythropoietin. Int Med 43:649–659CrossRefGoogle Scholar
  25. Jung YJ, Isaacs JS, Lee S et al (2003) IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J 17:2115–2117PubMedGoogle Scholar
  26. Kim AH, Khursigara G, Sun X et al (2001) Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 21:893–901CrossRefPubMedGoogle Scholar
  27. Koff JL, Shao MX, Kim S et al (2006) Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade. J Immunol 177:8693–8700PubMedGoogle Scholar
  28. Kuhlicke J, Frick JS, Morote-Garcia JC et al (2007) Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS One 2:e1364CrossRefPubMedGoogle Scholar
  29. Kwon SJ, Song JJ, Lee YJ (2005) Signal pathway of hypoxia-inducible factor-1alpha phosphorylation and its interaction with von Hippel-Lindau tumor suppressor protein during ischemia in MiaPaCa-2 pancreatic cancer cells. Clin Cancer Res 11:7607–7613CrossRefPubMedGoogle Scholar
  30. Lall H, Coughlan K, Sumbayev VV (2008) HIF-1alpha protein is an essential factor for protection of myeloid cells against LPS-induced depletion of ATP and apoptosis that supports Toll-like receptor 4-mediated production of IL-6. Mol Immunol 45:3045–3049CrossRefPubMedGoogle Scholar
  31. Lee KS, Kim SR, Park SJ et al (2008) Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1alpha-VEGF axis. Am J Respir Crit Care Med 178:787–797CrossRefPubMedGoogle Scholar
  32. Matsuzawa A, Saegusa K, Noguchi T et al (2005) ROS-dependent activation of the TRAF6-ASK1–p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol 6:587–592CrossRefPubMedGoogle Scholar
  33. Maxwell PH, Wiesener MS, Chang GW et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275CrossRefPubMedGoogle Scholar
  34. Medzhitov R, Janeway C Jr (2000) Innate immunity. N Engl J Med 343:338–344CrossRefPubMedGoogle Scholar
  35. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397CrossRefPubMedGoogle Scholar
  36. Min B, Paul WE (2008) Basophils and type 2 immunity. Curr Opin Hematol 15:59–63CrossRefPubMedGoogle Scholar
  37. Min B, Prout M, Hu-Li J et al (2004) Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J Exp Med 200:507–517CrossRefPubMedGoogle Scholar
  38. Mylonis I, Chachami G, Samiotaki M et al (2006) Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha. J Biol Chem 281:33095–33106CrossRefPubMedGoogle Scholar
  39. Nicholas SA, Sumbayev VV (2009) The involvement of hypoxia-inducible factor 1 alpha in Toll-like receptor 7/8-mediated inflammatory response. Cell Res 19:973–983CrossRefPubMedGoogle Scholar
  40. Nicholas SA, Sumbayev VV (2010) The role of redox-dependent mechanisms in the downregulation of ligand-induced Toll-like receptors 7, 8 and 4-mediated HIF-1alpha prolyl hydroxylation. Immunol Cell Biol 88:180–186CrossRefPubMedGoogle Scholar
  41. Nishi K, Oda T, Takabuchi S et al (2008) LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species-dependent manner. Antioxid Redox Signal 10:983–995CrossRefPubMedGoogle Scholar
  42. Oda T, Hirota K, Nishi K et al (2006) Activation of hypoxia-inducible factor 1 during macrophage differentiation. Am J Physiol Cell Physiol 291:C104–C113CrossRefPubMedGoogle Scholar
  43. Oh YT, Lee JY, Yoon H et al (2008) Lipopolysaccharide induces hypoxia-inducible factor-1 alpha mRNA expression and activation via NADPH oxidase and Sp1-dependent pathway in BV2 murine microglial cells. Neurosci Lett 431:155–160CrossRefPubMedGoogle Scholar
  44. Pacquelet S, Johnson JL, Ellis BA et al (2007) Cross-talk between IRAK-4 and the NADPH oxidase. Biochem J 403:451–461CrossRefPubMedGoogle Scholar
  45. Park HS, Yu JW, Cho JH et al (2004) Inhibition of apoptosis signal-regulating kinase 1 by nitric oxide through a thiol redox mechanism. J Biol Chem 279:7584–7590CrossRefPubMedGoogle Scholar
  46. Peyssonnaux C, Datta V, Cramer T et al (2005) HIF-1a expression regulates the bacterial capacity of phagocytes. J Clin Invest 115:1806–1815CrossRefPubMedGoogle Scholar
  47. Peyssonnaux C, Cejudo-Martin P, Doedens A et al (2007) Cutting edge: essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol 178:7516–7519PubMedGoogle Scholar
  48. Prabhakar NR, Kumar GK, Nanduri J (2009) Intermittent hypoxia-mediated plasticity of acute O2 sensing requires altered Red-Ox regulation by HIF-1 and HIF-2. Ann NY Acad Sci 1117:162–168CrossRefGoogle Scholar
  49. Prussin C, Metcalfe DD (2003) 4. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 111(2 suppl):S486–S494CrossRefPubMedGoogle Scholar
  50. Schroeder JT, MacGlashan DW Jr, Lichtenstein LM (2001) Human basophils: mediator release and cytokine production. Adv Immunol 77:93–122CrossRefPubMedGoogle Scholar
  51. Schwartzberg PL (2003) Amplifying Btk’s signal. Immunity 19:634–636CrossRefPubMedGoogle Scholar
  52. Semenza GL (2002) HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med 8(4 suppl):S62–S67CrossRefPubMedGoogle Scholar
  53. Siow YL, Au-Yeung KK, Woo CW et al (2006) Homocysteine stimulates phosphorylation of NADPH oxidase p47phox and p67phox subunits in monocytes via protein kinase Cbeta activation. Biochem J 398:73–82CrossRefPubMedGoogle Scholar
  54. Sumbayev VV (2008a) LPS-induced Toll-like receptor 4 signalling triggers cross-talk of apoptosis signal-regulating kinase 1 (ASK1) and HIF-1alpha protein. FEBS Lett 582:319–326CrossRefPubMedGoogle Scholar
  55. Sumbayev VV (2008b) PI3 kinase and direct S-nitrosation are involved in down-regulation of apoptosis signal-regulating kinase 1 during LPS-induced Toll-like receptor 4 signalling. Immunol Lett 115:126–130CrossRefPubMedGoogle Scholar
  56. Sumbayev VV, Yasinska IM (2006) Role of MAP kinase-dependent apoptotic pathway in innate immune responses and viral infection. Scand J Immunol 63:391–400CrossRefPubMedGoogle Scholar
  57. Sumbayev VV, Yasinska IM (2007) Mechanisms of hypoxic signal transduction regulated by reactive nitrogen species. Scand J Immunol 65:399–406CrossRefPubMedGoogle Scholar
  58. Sumbayev VV, Budde A, Zhou J et al (2003) HIF-1 alpha protein as a target for S-nitrosation. FEBS Lett 535:106–112CrossRefPubMedGoogle Scholar
  59. Sumbayev VV, Nicholas SA, Streatfield CL et al (2009) Involvement of hypoxia-inducible factor-1 in IgE-mediated primary human basophil responses. Eur J Immunol 39:3511–3519CrossRefPubMedGoogle Scholar
  60. Viemann D, Schmidt M, Tenbrock K et al (2007) The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol 178:3198–3207PubMedGoogle Scholar
  61. Walmsley SR, Cadwallader KA, Chilvers ER (2005) The role of HIF-1alpha in myeloid cell inflammation. Trends Immunol 26:434–439CrossRefPubMedGoogle Scholar
  62. Yarovinsky F, Zhang D, Andersen JF et al (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626–1629CrossRefPubMedGoogle Scholar
  63. Yasinska IM, Kozhukhar AV, Sumbayev VV (2004) S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide system activates apoptosis signal-regulating kinase 1. Arch Biochem Biophys 428:198–203CrossRefPubMedGoogle Scholar
  64. Yuan G, Nanduri J, Khan S et al (2008) Induction of HIF-1alpha expression by intermittent hypoxia: involvement of NADPH oxidase, Ca2+ signalling, prolyl hydroxylases, and mTOR. J Cell Physiol 217:674–685CrossRefPubMedGoogle Scholar
  65. Zarember KA, Malech HL (2005) HIF-1alpha: a master regulator of innate host defenses? J Clin Invest 115:1702–1704CrossRefPubMedGoogle Scholar
  66. Zhou G, Golden T, Aragon IV et al (2004) Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade. J Biol Chem 279:46595–46605CrossRefPubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2010

Authors and Affiliations

  1. 1.Medway School of PharmacyUniversity of KentKentUK

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